Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable to obtain seizure freedom using the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE).
Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan et al., 2009).
Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment-resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from, an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILAE classification described below and in FIG. 1.
The International classification of seizure types proposed by the ILAE was adopted in 1981 and a revised proposal was published by the ILAE in 2010 and has not yet superseded the 1981 classification. FIG. 1 is adapted from the 2010 proposal for revised terminology and includes the proposed changes to replace the terminology of partial with focal. In addition the term “simple partial seizure” has been replaced by the term “focal seizure where awareness/responsiveness is not impaired” and the term “complex partial seizure” has been replaced by the term “focal seizure where awareness/consciousness is impaired”.
From FIG. 1 it can be seen that Generalised seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence (petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizures and Myoclonic Seizures.
Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness/responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a Bilateral convulsive seizure, which is the proposed terminology to replace Secondary Generalized Seizures (generalized seizures that have evolved from focal seizures and no longer remain localized).
Focal seizures where the subject's awareness/responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
Epileptic syndromes often present with many different types of seizure and identifying the types of seizure that a patient is suffering from is important as many of the standard AED's are targeted to treat or are only effective against a given seizure type/sub-type.
One such childhood epilepsy is Sturge Weber syndrome (SWS). SWS is a congenital, non-familial disorder of unknown incidence. It is caused by a somatic genetic mutation in the gene GNAQ. It is characterized by a congenital facial birthmark and neurological abnormalities. Other symptoms associated with SWS can include eye and internal organ irregularities.
The clearest indication of SWS is a facial birthmark or “Port Wine Stain” which is present from birth. This typically involves at least one upper eyelid and the forehead.
Neurological problems are caused by the development of excessive blood vessel growth on the surface of the brain. These are located typically on the back region of the brain on the same side as the port wine birthmark. These growths create abnormal conditions for brain function in the region.
Epilepsy is the most common early problem, (in around 80% of children with SWS), often starting by one year of age. The convulsions usually appear on the opposite side of the body from the port wine stain and vary in severity. A weakening or loss of the use of one side of the body may develop opposite to the port wine stain. Developmental delay of motor and cognitive skills may also occur to varying degrees.
Other problems such as visual field defects, glaucoma and headaches often occur in addition to neurological problems.
The anticonvulsant medications used to treat seizures in SWS include carbamazepine; valproate; acetazolamide; diazepam; phenytoin; felbamate; tiagabine; levetiracetam; clonazepam; lamotrigine; primidone; gabapentin; phenobarbital; ethosuximide and zonisamide and topiramate.
Management of the non-seizure symptoms in SWS are also required.
Common AED defined by their mechanisms of action are described in the following tables:
TABLE 1Examples of narrow spectrum AEDNarrow-spectrumAEDMechanismIndicationPhenytoinSodium channelComplex partialTonic-clonicPhenobarbitalGABA/Calcium channelPartial seizuresTonic-clonicCarbamazepineSodium channelPartial seizuresTonic-clonicMixed seizuresOxcarbazepineSodium channelPartial seizuresTonic-clonicMixed seizuresGabapentinCalcium channelPartial seizuresMixed seizuresPregabalinCalcium channelAdjunct therapy for partialseizures with or withoutsecondary generalisationLacosamideSodium channelAdjunct therapy for partialseizuresVigabatrinGABASecondarily generalizedtonic-clonic seizuresPartial seizuresInfantile spasms due toWest syndrome
TABLE 2Examples of broad spectrum AEDBroad-spectrumAEDMechanismIndicationValproic acidGABA/Sodium channelFirst-line treatment for tonic-clonic seizures, absenceseizures and myoclonicseizuresSecond-line treatment forpartial seizures and infantilespasms.Intravenous use in statusepilepticusLamotrigineSodium channelPartial seizuresTonic-clonicSeizures associated withLennox-Gastaut syndromeEthosuximideCalcium channelAbsence seizuresTopiramateGABA/Sodium channelSeizures associated withLennox-Gastaut syndromeZonisamideGABA/Calcium/SodiumAdjunctive therapy in adultschannelwith partial-onset seizuresInfantile spasmMixed seizureLennox-Gastaut syndromeMyoclonicGeneralised tonic-clonicseizureLevetiracetamCalcium channelPartial seizuresAdjunctive therapy for partial,myoclonic and tonic-clonicseizuresClonazepamGABATypical and atypical absencesInfantile myoclonicMyoclonic seizuresAkinetic seizuresRufinamideSodium channelAdjunctive treatment ofpartial seizuresassociated withLennox-Gastaut syndrome
TABLE 3Examples of AED used specifically in childhood epilepsyAEDMechanismIndicationClobazamGABAAdjunctive therapy in complexpartial seizuresStatus epilepticusMyoclonicMyoclonic-absentSimple partialComplex partialAbsence seizuresLennox-Gastaut syndromeStiripentolGABASevere myoclonic epilepsy ininfancy (Dravet syndrome)
Over the past forty years there have been a number of animal studies on the use of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures. For example, Consroe et al., (1982) determined that CBD was able to prevent seizures in mice after administration of pro-convulsant drugs or an electric current.
Studies in epileptic adults have also occurred in the past forty years with CBD. Cunha et al. reported that administration of CBD to eight adult patients with secondary generalized epilepsy resulted in a marked reduction of seizures in 4 of the patients (Cunha et al., 1980).
A study in 1978 provided 200 mg/day of pure CBD to four adult patients, two of the four patients became seizure free, whereas in the remainder seizure frequency was unchanged (Mechoulam and Carlini, 1978).
In contrast to the studies described above, an open label study reported that 200 mg/day of pure CBD was ineffective in controlling seizures in twelve institutionalized adult patients (Ames and Cridland, 1986).
Based on the fact that chronologically the last study to look at the effectiveness of CBD in patients with epilepsy proved that CBD was unable to control seizures, there would be no expectation that CBD might be useful as an anti-convulsant agent.
In the past forty years of research there have been over thirty drugs approved for the treatment of epilepsy none of which are cannabinoids. Indeed, there appears to have been a prejudice against cannabinoids, possibly due to the scheduled nature of these compounds and/or the fact that THC, which is a known psychoactive, has been ascribed as a pro-convulsant (Consroe et al., 1977).
The patent applications GB 2,487,712 describes the use of CBD with anti-epileptic drugs and WO 2015/193667 describes the use of CBD in the treatment of treatment resistant epilepsy, in particular patients with FIRES are shown to benefit particularly from the treatment.
A paper published recently suggested that cannabidiol-enriched cannabis may be efficacious in the treatment of epilepsy. Porter and Jacobson (2013) report on a parent survey conducted via a Facebook group which explored the use of cannabis which was enriched with CBD in children with treatment-resistant epilepsy. It was found that sixteen of the 19 parents surveyed reported an improvement in their child's epilepsy. The children surveyed for this paper were all taking cannabis that was purported to contain CBD in a high concentration although the amount of CBD present and the other constituents including THC were not known for many of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6 mg/kg/day (in those extracts tested), THC levels as high as 0.8 mg/kg/day were reported.
A paper by Press et al. (2015) describes a review of 75 children and adolescents provided with oral cannabis extract. The responder rate for patients with Lennox-Gastaut syndrome was very high at 88.9%, whereas the rate for other childhood epilepsy syndromes such as Doose syndrome and Dravet syndrome were much lower or showed no improvement at all.
Providing children with TRE with a cannabis extract that comprises THC, which has been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose of 0.8 mg/kg/day, is a concern and as such there is a need to determine whether CBD is in fact efficacious.
More recently in March 2016, GW Pharmaceuticals announced positive results in a Phase 3 study of CBD in the treatment of Dravet syndrome.
To date there have been no trials of CBD in children and young adults with Sturge Weber syndrome.